The germ-line genetic variants identified thus far generally explain only part of the predicted genetic risk for most cancers, including renal cell carcinoma (RCC). A component of the remaining risk may be explained by functionally consequent genetic variants that are individually very rare (or private). The contribution that thi spectrum of genetic variation makes to susceptibility to RCC remains unexplored. Strategies that allow for agnostic, genome-wide assessment of such variants are likely to require very important sample sizes for adequate statistical power. In addition to the large cost, such study approaches may not be practical for rare cancers due to the lack of sufficiently large bio-repositories. Unusual frequencies of two-hit mutation events (one mutation in the germ-line, and a second, somatic mutation in the same individual) may be able to map genes involved in RCC cancer susceptibility. Within the exceptional IARC RCC bio-repository, we propose to use this two-hit mapping approach in a discovery and replication study design to identify genes involved in genetic susceptibility to RCC acting via Knudson's two hit model.